Recent findings have focused attention on amyloid beta-peptide (Abeta) as a key element in the pathogenicity of cell stress and, ultimately, cytotoxicity to neurons and the vasculature in Alzheimer's disease and cerebrovascular amyloid angiopathy. Although dense extracellular plaque-like deposits of Abeta are abundant late in the course of Alzheimer's disease, it has become evident that much earlier events in the generation and toxicity of Abeta, especially within the endoplasmic reticulum, will be critical to fully understand in order to design therapies that block the disease at a stage when cellular dysfunction is still reversible. Biology of the presenilins, cell surface and intracellular targets of Abeta converge on microglial-neuronal interactions and the vasculature to create a milieu of sustained and destructive inflammation, as well as an exaggerated and adverse response to ischemic stress. Insights from new animal models and clinical studies will be described, and related to an emerging cell biology of Alzheimer's disease and cerebrovascular amyloid angiopathy; namely, that of cellular dysfunction is driven by Abeta-induced engagement of specific molecular targets, rather than the previously held notion of passive cellular disruption by massive fibrils nonspecifically and inexorably destabilizing cell membranes. This altered view of the pathogenesis of Alzheimer's disease suggests multiple sites for future therapeutic interventions.